tbuckley/cabot-search huggingface dataset:
Management (mgmt) of futibatinib-associated adverse events (AEs) in patients (pts) with advanced cancers: Results of a pooled analysis.
Authors: Funda Meric-Bernstam, Antoine Hollebecque, Junji Furuse, Do-Youn Oh, John A. Bridgewater, Masashi Shimura, Bailey Anderson, Nanae Hangai, Volker Wacheck, Lipika Goyal
Journal: Journal of Clinical Oncology (2023)

586 Background: Futibatinib, a covalently binding FGFR1–4 inhibitor, showed a 42% objective response rate with a 9.7 mo median duration of response in pts with advanced intrahepatic cholangiocarcinoma (iCCA) and FGFR2 fusions/rearrangements in the phase 2 FOENIX-CCA2 trial. Futibatinib treatment (tx) was safe and tolerable with a predictable and manageable side effect profile. This pooled retrospective analysis examined mgmt of futibatinib-associated AEs in pts with advanced tumors, including iCCA. Methods: Pts from a global phase 1/2 study (NCT02052778) and a Japanese phase 1 study (JapicCTI-142552) who received futibatinib 20 mg QD (recommended dose) were included. Futibatinib dose modifications and supportive medications (meds) for AE mgmt were analyzed for futibatinib-associated AEs of clinical interest (group terms: hyperphosphatemia, hepatic AEs, retinal disorders, nail disorders, rash, palmar plantar erythrodysesthesia [PPE], cataract). The Kaplan-Meier method was used for time-to-resolution (TTR) analysis. Results: As of October 1, 2020, 318 pts with advanced solid tumors (60% CCA; 98% with ≥1 prior tx) had received ≥1 futibatinib 20 mg QD dose (median tx duration, 3.6 mo). Table includes incidence and mgmt of key AEs of clinical interest. Hyperphosphatemia was the most frequent cause of futibatinib dose modifications; 85% and 30% of pts with hyperphosphatemia received phosphate binders and/or phosphaturic agents, respectively, with no obvious TTR differences. Other common supportive meds included analgesics (in 55% of pts with nail disorders; 71% with PPE) and corticosteroids (37% of pts with rash). Retinal disorders occurred in 8% of pts (all grade [gr] 1-2 and resolved). Cataract, a late-onset AE on continued tx, occurred in 12 (4%; 4 [1%] gr ≥3) pts, leading to dose modifications in 3 pts. One pt underwent cataract surgery and resumed futibatinib tx the next day. Discontinuations due to tx-related AEs were rare (2.5%) and included 1 pt each with retinal detachment, onycholysis, and cataract. Conclusions: This analysis of AE mgmt showed a consistent and manageable safety profile for futibatinib in pts with pretreated advanced tumors. Commonly observed AEs with futibatinib were well managed with dose adjustments and supportive meds and rarely led to tx discontinuation. Clinical trial information: NCT02052778 /JapicCTI-142552. [Table: see text]
Downstaging locally advanced hepatocellular carcinoma with selective internal radiation therapy.
Authors: Marjorie Hoang, Pierce K. H. Chow
Journal: Journal of Clinical Oncology (2023)

536 Background: Locally advanced HCC (beyond BCLC A, including PVT but without extra-hepatic metastases) that are unresectable because of inadequate future liver remnant may be downstaged by selective internal radiation therapy (SIRT) with Yttrium-90 to subsequently receive interval surgical resection. We hypothesized that HCC that required downstaging before resection will have some disparity in overall survival (OS) and recurrence-free survival (RFS) compared to HCCs that were resected upfront. Methods: We reviewed all patients who underwent surgical resection for HCC between 1 st January 2000 and 31 st December 2019 and identified those that had locally advanced HCC and were downstaged with Y90-SIRT and referred for consideration of surgical resection. OS and RFS of patients resected upfront for early and locally advanced HCC and those resected after downstaging were obtained using the Kaplan Meier method and compared using Log-rank (Mantel-Cox) test after propensity score matching. Results: 1141 patients had surgical resection for HCC within the study period. 245 patients were excluded for other primary cancers or metastatic disease at diagnosis. 875 were resected upfront (473 early, 402 locally advanced) and 23 locally advanced HCC were downstaged with SIRT before resection. Locally advanced HCC patients downstaged with Y90 before resection have significantly better OS and RFS than locally advanced HCC with upfront resection (5-year OS of 69.0% versus 47.5% p = 0.048; 5-year RFS of 53.5% vs 27.0%, p = 0.047) and similar OS and RFS with resected early HCC (5-year OS of 69.0% versus 62.6% p=0.475; 5-year RFS of 53.5% vs 39.0%, p = 0.736). Conclusions: In addition to downstaging HCC to resection, Y90-SIRT also produces a change in tumour biology that favours better prognosis. A randomised controlled trial to the role of SIRT as neoadjuvant therapy in locally advanced HCC is justified and can potentially change practice.
Total neoadjuvant oxaliplatin-based therapy (TNT) before (induction) and after (consolidation) chemoradiation for advanced rectal cancer: MRI correlation on complete response and outcome.
Authors: Putao Cen, Kok Hoe Chan, Jeffrey Van Eps, Julie Haewon Rowe, Curtis Jackson Wray
Journal: Journal of Clinical Oncology (2023)

165 Background: Preoperative chemoradiation with fluoropyrimidine, followed by total mesorectal excision (TME) and adjuvant chemotherapy is the standard care for locally advanced rectal cancer (LARC). Studies have shown the potential benefit of oxaliplatin based TNT approach. The benefits of using of both induction and consolidation chemotherapy with chemoradiation prior of TME is not well studied. We investigate whether the use of oxaliplatin based before (induction) and after (consolidation) neoadjuvant chemoradiation will increase the pCR and clinical Complete response (cCR), improve survival and MRI correlation. Methods: Patients treated with curative intent surgery for LARC who received oxaliplatin based induction and consolidation chemotherapy with neoadjuvant capecitabine chemoradiation were identified. Demographics and clinicopathologic data were analyzed. Multiparametric MRI was used for initial staging and restaging before surgery. The primary endpoint will be the complete response (pathological and clinical), recurrent-free survival (RFS), and overall survival (OS). Results: A total of 21 patients have been identified, all patient has T3/T4 and positive nodes N1/N2 on initial MRI staging, 2 (10%) patients had Stage IV disease with abdominal para-aortic nodes. Median age was 63 (range: 26-76); 14 (67%) male. As for the induction regimen, 9 (43%) had CAPOX/FOLFOX, 7 (33%) had short-course capecitabine, 5 (24%) had FOLFIRINOX. All patient received neoadjuvant chemoradiation with capecitabine. As for consolidation, 19 (90%) had CAPOX/FOLFOX, 1 (5%) had capecitabine and 1 (5%) had FOLFIRINOX. Median time for induction and consolidation chemotherapy was 8.5 weeks (range: 1-24) and 8 weeks (range: 2-16) respectively. Median time from starting induction chemotherapy to surgery was 6.8 months (range: 3.2-11). Eight (38%) patients had cCR and pCR. Post-treatment restaging MRI prior of resection has 100% concordant rate with pCR. All (100%) pateints had tumor downstaged after treated with TNT and chemoradiation. The sensitivity of MRI in detecting the residual lymph node post TNT/neoadjuvant chemoradiation was 55% (95% CI: 26-81%), and the negative predictive value was 75% (51-90%); the specificity was 100% (76-100%) and the positive predictive value was 100% (57-100%). There is no death and one patient had recurrence after recurrence free for 2 years. Median RFS and OS are not meet. Median follow up time is 25.7 months (range: 9.1-76.8). Conclusions: Neoadjuvant oxaliplatin based therapy before and after chemoradiation for rectal cancer potentially improves CR rate, and accurately predicted by post-treatment MRI. The use of MRI can potentially help to select candidates who desire organ preservation.
Inhibition of gastric cancer by a new controlled releasing compound of TLR-7/8 agonist via immune activation in a gastric cancer xenograft mice model.
Authors: Hyun Myong Kim, Kyoungyun Jeong, Jaeun Yoo, Yie-Ri Yoo, Ji-Yeon Shin, Leena Lim, Juhee Jeong, Changhwan Yoon, Sandra Ryeom, Sam S. Yoon, Do Joong Park, Hyuk-Joon Lee, Han-Kwang Yang, Do-Youn Oh, Keehoon Jung, Yong Taik Lim, Seong-Ho Kong
Journal: Journal of Clinical Oncology (2023)

420 Background: TLR-7/8 agonist has been suggested to be an effective immunotherapeutic agent, possible systemic side effect has forbid its clinical usage. A new controlled-releasing compound of TLR-7/8 agonist was developed to overcome the limitations, and this study aimed to evaluate efficacy and safety of this new compound in xenograft mouse model using cell-lines derived from triple conditional (Tcon) mouse which develop gastric cancer spontaneously. Methods: A cell line was established by tumor tissue in Tcon mouse which was developed by activation of Kras and suppression of E-cadherin and P53. Tcon cell line was evaluated its growth rate, sensitivity to anticancer agents and in vivo tumorigenicity. Tcon cell line was subcutaneously injected to the flank of the syngeneic mice, and 5-FU and/or TLR-7/8 agonist were administered into 4 groups of mice (control group, 5-FU alone, TLR-7/8 agonist alone, and combination of 5-FU and TLR-7/8). 5-FU was administered i.p(intra-peritoneal) in once a week and TLR-7/8 agonist was injected i.t(intra-tumoral) 3 times a week. Tumor size and mouse weight were measured for drug efficacy and safety. Immune profile of the tumor was analyzed by fluorescence-activated cell sorting. Results: Tcon cell-line show a rapid growth with 24 hours of doubling time, and good in vivo tumorigenicity in syngeneic mice. Cell-line showed moderate sensitivity to 5-FU and paclitaxel but resistance to oxaliplatin. Tumors in 5-FU alone group showed slight decrease in size compared with that in control group, However, TLR-7/8 agonist alone and combination significantly inhibited tumor growth. Weight loss or any significant side effect was not observed in any group. In immune profiling, TLR-7/8 mono or combination group showed increased levels of infiltrating CD4, CD8 T cells, and recruited NK cell as well as significantly increase M1/M2 ratio of macrophages compared to 5-FU alone or control group. Conclusions: A new controlled releasing system of TLR-7/8 agonist with or without 5-FU showed a excellent tumor inhibition efficacy with low toxicity in gastric cancer xenograft model. The effect seemed to be through multiple immune activations including cell-mediated immune response, M1 macrophage polarization as well as innate NK cells.
Health-related quality of life in patients with <i>RAS</i> wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: An analysis of the Panama trial (AIO KRK0212).
Authors: Alexej Ballhausen, Meinolf Karthaus, Stefan Fruehauf, Ullrich Graeven, Lothar Mueller, Alexander Koenig, Ludwig Fischer von Weikersthal, Greta Sommerhäuser, Annabel Helga Sophie Alig, Eray Goekkurt, Siegfried Haas, Annika Kurreck, Arndt Stahler, Swantje Held, Anke C. Reinacher-Schick, Stefan Kasper, Volker Heinemann, Sebastian Stintzing, Tanja Trarbach, Dominik Paul Modest
Journal: Journal of Clinical Oncology (2023)

51 Background: The PANAMA study demonstrated superior progression-free survival (PFS) with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. We report health-related quality of life (HRQOL) analyses of the PANAMA study. Methods: HRQOL was assessed by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression. All patients who received at least one dose of induction therapy and completed at least one HRQOL assessment were included into the analysis. HRQOL outcomes were mean changes in EORTC QLQ-C30 from baseline (prior to cycle 1 of induction therapy) to each cycle of treatment (both induction and maintenance therapy). The trial is registered with ClinicalTrials.gov (NCT01991873). Results: In total, 349/377 (93%) of the induction and 237/248 pts (96%) of the maintenance group completed at least one HRQOL assessment and were included in the HRQOL analysis population. There were no significant differences in any of the EORTC QLQ-C30 items between both treatment arms before induction therapy and at randomization. From baseline to cycle 6 of induction therapy there was significant improvement in mean EORTC QLQ-C30 global health status (GHS)/QOL, functioning (except for cognitive functioning) and symptom (except for nausea and vomiting, dyspnea, appetite loss, constipation, and financial difficulties) scores in the randomized population. During maintenance therapy, no significant differences between FU/FA plus Pmab and FU/FA alone were observed. In both arms of the trial, GHS/QOL scores were maintained or trended to improve from baseline (start of induction therapy) to cycle 10 of maintenance therapy (FU/FA plus Pmab: mean difference 9.48 [95% CI 1.96-17.00]; p=0.014); FU/FA arm (mean difference 6.52 [95% CI –1.9-14.95]; p=0.128). Conclusions: Using the established EORTC QLQ-C30 assessment, the addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer did not impair the HRQOL endpoints analyzed compared to FU/FA alone. These results, along with previously reported improvement in PFS, may support clinical decision-making concerning maintenance treatments. Clinical trial information: NCT01991873 .
Liver-directed therapy of neuroendocrine liver metastases.
Authors: Léamarie Meloche-Dumas, Frédéric Mercier, Tori Barabash, Calvin Law, Simron Singh, Sten Myrehaug, Wing Chan, Julie Hallet
Journal: Journal of Clinical Oncology (2023)

647 Background: While there have been major advances in the care of neuroendocrine tumors (NETs), there is still no widely adopted therapeutic sequencing in metastatic NETs. The roles and benefits of locoregional treatments need reassessment, in order to define a modern therapeutic algorithm. We examined contemporary short-term outcomes of liver-directed therapy for metastatic NETs. Methods: We conducted a population-based retrospective cohort study of patients with metastatic NETs (2000-2019) undergoing liver embolization (LE) or liver resection (LR). Outcomes were 30-day major morbidity (Clavien-Dindo grade 3-5) and/or re-admission (composite) and length of hospital stay. Modified Poisson regression accounting for clustering at the hospital level examined factors associated with outcomes in both treatment groups. Results: Overall, 1,224 LEs and 502 LRs were performed for 5,159 patients with metastatic NETs. Median length of hospital stay was 1 day (IQR 1-4) for liver embolization and 7 days (IQR 5-9) for liver resection. 30-day major morbidity and re-admission occurred after 213 LEs (17.4%) including 40 (3.3%) deaths, and 138 LRs (27.5%) including 11 (2.2%) deaths. There were 25 (2%) LEs followed by infectious complications. Factors independently associated with increased risk after LE were prior LE treatment (adjusted relative risk- aRR 0.62; 95%CI 0.44-0.88), rural residence (aRR 0.43; 95%CI 0.20-0.91) and high comorbidity burden (aRR 1.85; 95%CI 1.34-2.54). The only factor independently associated with increased risk after LR was metachronous metastases (RR 0.60; 95%CI 0.37-0.98). Conclusions: In this contemporary cohort, LE was associated with mortality similar to that of LR. Prior LE, rural residence, comorbidities, and metachronous metastatic diagnosis were associated with higher risk of major morbidity and re-admission. This information is important when discussing the use of and choice of liver-directed therapies in the multi-disciplinary management of metastatic NETs. Further characterization of long-term outcomes and patient-reported outcomes will further support decision-making, counselling, and patient preparation.
Genomic alterations associated with resistance to EGFR monoclonal antibodies (mAb) in real-world patients with metastatic colorectal cancer (mCRC).
Authors: Samuel J Klempner, Julia C. F. C. F. Quintanilha, Matthew Emmett, Ryon Graf, Alexa Betzig Schrock, Hanna Tukachinsky, Geoffrey R. Oxnard, Parvathi Myer
Journal: Journal of Clinical Oncology (2023)

52 Background: mCRC patients with RAS and BRAF mutant tumors do not benefit from treatment with EGFR mAb. However, some RAS/BRAF wild-type patients do not benefit from EGFR mAbs. We sought to investigate additional primary and acquired biomarkers of resistance to EGFR mAb in mCRC. We hypothesized (1) alterations in pre-specified genes of known biological but unconfirmed clinical significance are associated with less favorable outcomes in patients treated with EGFR mAb; (2) these alterations are acquired during treatment and are associated with the time of exposure to these drugs. Methods: We included mCRC patients with RAS/ BRAF wild-type tumors receiving EGFR mAb (cetuximab or panitumumab) in 1 st line (1L, n = 248) or in 2L+ of therapy (n = 2,118). This study used the US-based de-identified Flatiron Health-Foundation Medicine real-world mCRC clinico-genomic database, originating from ~280 US cancer clinics between 01/2011 and 04/2022. Pre-specified genes included PIK3CA, PTEN, MAP2K1, and RTKs. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between patients +/- alterations by Cox models, adjusted for a risk score generated from known clinical prognostic features. Alterations were compared between patients with biopsies collected before and after starting treatment with EGFR mAb by chi-square, adjusted for multiple comparisons. The association between the amount of time on drug exposure and alterations was evaluated by linear regression. Results: Patients with RTK/ MAP2K1 alterations (n = 38, 15.3%) had less favorable outcomes (PFS HR 1.83, 95% CI 1.27-2.65, p = 0.001/ OS HR 1.59, 95% CI 1.00-2.51, p = 0.048). The same trend was observed for patients with PIK3CA/ PTEN alterations (n = 31, 12.5%, PFS HR 1.35, 95% CI 0.89-2.03, p = 0.155/ OS HR 1.75, 95% CI 1.08 -2.85, p = 0.024) and ERBB2amp (n = 21, 8.5%, PFS HR 1.52, 95% CI 0.93-2.5, p = 0.096/ OS HR 1.33, 95% CI 0.71-2.5, p = 0.373). Compared to biopsies obtained before (n = 1,834), those obtained after treatment initiation were enriched for RTK alterations (n = 284, +9%, p = 0.001), especially for METamp (+3%, p = 0.04). Compared to unexposed patients, patients exposed to EGFR inhibitors had higher odds (p &lt; 0.001) of developing RTK alterations (OR: 1.84, 95% CI 1.54-2.19; OR 3.33, 95% CI 2.60-4.24; and OR 2.28, 95% CI 1.56-3.26 for 0-12, 12-24, and 24+ months of exposure, respectively). Additional analyses will be presented. Conclusions: RAS/RAF WT mCRC patients with baseline alterations in RTK genes have less favorable outcomes on EGFR inhibitors (intrinsic resistance), and post-EGFR mAb samples (acquired resistance) converge around RTK and MAPK alterations, particularly MET, in real-world data.
Long-term survival outcome of multi-institutional prospective phase II trial of conversion surgery: CCOG1403.
Authors: Seiji Ito, Yuichi Ito, Daisuke Kobayashi, Hidenobu Matsushita, Yuri Tanaka, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2023)

380 Background: From the result of CONVO-GC-1, safety and efficacy of conversion surgery are shown. But there are few prospective studies about conversion surgery. We conducted multi-institutional prospective study of conversion surgery (CCOG1403). Methods: The patients (pts) with gastric cancer, who were initially regarded as non-curable and curably resectable after at least one course of chemotherapy, were enrolled. After diagnostic laparoscopy or laparotomy, pts were performed gastrectomy in case of curably resectable. The primary endpoint was 3-year survival from the start of first line chemotherapy. The planned sample size was 30, with one-sided alpha of 5%, power of 90%, expected 3-year survival rate of 27%, and threshold of 7%. Secondary endpoints were 5-year survival from the start of first line chemotherapy, the proportion of R0 resection, 3-year survival from the conversion surgery, pathological response, and adverse events. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000014251. Results: From April 2014 to March 2019, 30 pts were enrolled from 7 institutions. The mean age was 66.7. Non-curable factors were PER(11), LYM(9), HEP(6), T(4), CY(1), PUL(1), BRA(1), and other(1), respectively. Four pts had more than one non-curable factors. The categories of Yoshida’s classification were Cat.1(3), Cat.2(16), Cat.3(8), and Cat.4(2). Regimen of chemotherapy were SOX (11), SP (8), XP+HER (8), PTX ip containing regimen (6), and others (12). Clinical responses of preoperative chemotherapy were PR in 24 and SD in 6. Operative procedures were TG (18), DG (7), and PG (1). Median operative time was 278.5min. and median blood loss was 417.5ml. Twenty-four (80%) pts achieved R0 resection. Five pts suffered &gt;= C-D Grade III postoperative complication but all pts recovered. The pathological finding revealed major response, defined as disappearance more than two third of the primary tumor, in 26.7% (8/30) pts. Twenty-seven (90%) pts received postoperative chemotherapy. Among 24 pts with R0 resection, 16 pts experienced recurrence in PER(5), LYM(4), HEP(4), PUL(3), BRA(1), and others(4). In 30 pts accrued, 19 (66.3% 43.9-80.1), 16 (55.3% 34.3-71.7) survived more than 3 years from the start of first line chemotherapy and the conversion surgery, respectively. Conclusions: Conversion surgery is effective and worth for testing in the following randomized trial. Clinical trial information: UMIN000014251 .